CHEMISTRY CORE The Chemistry Core is the central component of this proposal and will be responsible for engaging in accelerated probe development programs with Specialty Screening and Comprehensive Centers, employing TES and medicinal chemistry design principles in probe development, integrating cheminformatics and computational chemistry into HTS triage and probe design, executing large scale synthesis of probe molecules, developing advanced molecular tools and providing training for TES, parallel synthesis and medicinal chemistry across the MLPCN. The Chemistry Core will work closely with Informatics and Administrative Core to ensure MLPCN goals are met. The following specific aims summarize the major functions of the chemistry core: AIM 1. To rapidly develop high quality probe molecules employing TES and medicinal chemistry design principles with input from, and analysis with, computational chemistry tools, and to submit all compounds synthesized to the MLSMR on a quarterly basis. AIM 2. To employ our internal ADME/DMPK component along with in silico methods to further optimize high quality MLPCN probe molecules . AIM 3. To perform large scale synthesis (>5 g) of probe molecules developed both at Vanderbilt and across the MLPCN and optimize compound formulation. AIM 4. To collaborate with the Informatics Core for the overlapping responsibility of compound registration and compound management. AIM 5. To train chemists across the MLPCN in the art of TES and parallel synthesis to accelerate probe development at other Chemistry and Comprehensive Centers.